DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments to the claims and arguments filed on March 5, 2026 have been received and entered. Claims 50, 54 and 55 have been amended. Claims 50-60 are pending in the instant application.
Election/Restrictions
Applicant’s election of SEQ ID NO: 16, 21 and cancer as species of at least one ribonucleic acid and disorder in the reply filed on October 3, 3025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Priority
This application is a Divisional of US application no 15/524,968 05/05/2017, which is a 371 of PCT/US15/59621 filed on 11/06/2015 that claims priority from US provisional application no 62/076,424 filed on 11/06/2014.
Claims 50-60 are under consideration.
Maintained- Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 50 -60 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
The claims are directed to a method f method of administering cells to a subject in need of such cells, the method comprising:(a) altering a target polynucleotide sequence associated with the disorder in a cell or a population of cells ex vivo by contacting the polynucleotide sequence with a clustered regularly interspaced short palindromic repeats-associated (Cas) protein and at least one ribonucleic acid, wherein the ribonucleic acid directs Cas protein to and hybridizes to a target motif of the target polynucleotide sequence associated with the disorder, wherein the target polynucleotide sequence associated with the disorder is cleaved;(b) altering a target B2M polynucleotide sequence in the cell or population of cells ex vivo by contacting the target B2M polynucleotide sequence with a clustered regularly interspaced short palindromic repeats-associated (Cas) protein and at least one ribonucleic acid selected from the group consisting of SEQ ID NOs: 9-23 and 419-2609; and(c) administering the cell or population of cells into the subject. Dependent claim limits the disorder selected from the group consisting of a genetic disorder, an infection, and cancer (claim 52) subsequently limiting to HIV or AIDS. Claim 53 is directed to a method of claim 50 further comprising altering one or more additional polynucleotide sequences in the cell ex vivo. Claims 54-55 limit the Cas protein comprises a Cas9 protein or a functional portion thereof or a Cpfl protein. Claim 56 limits the cell or population of cells are selected from the group consisting of a stem cell, a pluripotent cell, a progenitor cells, a hematopoietic stem and/or progenitor cell, a CD34+ mobilized peripheral blood cell, a CD34+ cord blood cell, a CD34+ bone marrow cell, a CD34+CD38-Lineage-CD90+CD45RA- cell, and a CD34+ hematopoietic stem and/or progenitor cell; a CD4+ T cell, a hepatocyte, a somatic cell, and a non-transformed cell. Claim 58 limit the method of claim 50, wherein the alteration of the target B2M polynucleotide sequence in the cell or population of cells results in the deletion of a contiguous stretch of genomic DNA, thereby eliminating surface expression of MHC Class I molecules in the cell or population of cells.
Breadth of the claims:
The breadth of the claimed invention encompasses administering any genetically modified cells to a subject in need of such cells. The claims are broadly directed to (a) altering any target polynucleotide sequence associated with a broad class of disorder in a cell or a population of cells ex vivo by contacting the polynucleotide sequence with a Cas protein and at least one ribonucleic acid, wherein the ribonucleic acid directs Cas protein to and hybridizes to a target motif of the target polynucleotide sequence associated with the disorder, wherein the target polynucleotide sequence associated with the disorder is cleaved; (b) altering a target B2M polynucleotide sequence in the cell or population of cells ex vivo by contacting the target B2M polynucleotide sequence with a Cas protein and at least one ribonucleic acid selected from the group consisting of SEQ ID NOs: 9-23 and 419-2609 and (c) introducing the cell or population of cells into the subject in need thereof such cells.
The specification broadly discusses cells of the invention to be used in autologous cell , xenogeneic cell (para.143), allogenic transplantation (para. 3) and " adoptive immunotherapy " (para. 238). All of the contemplated cell therapies are for the treatment of a disease and/or disorder and thus the skilled artisan would find that the claimed method of introducing a cell or a population of cells to a subject in need thereof thus would encompass treating said subject for a disorder.
It is noted that although instant claims have been amended to recite a method of administering cells to a subject in need of such cells, comprising (a) altering any target polynucleotide sequence associated with a broad class of disorder in a cell or a population of cells ex vivo (b) altering a target B2M polynucleotide sequence in the cell or population of cells ex vivo by contacting the target B2M polynucleotide sequence with a Cas protein and at least one ribonucleic acid and administering the cell or population of cells via any route into the subject in need thereof such cell, they have been analyzed for their intended use in the subject in need thereof suffering from, being treated for, diagnosed with, suspected of having, or at increased risk of developing, the disorder such as a genetic disorder, an infection (e.g., HIV or AIDS), and cancer. The cells can also be obtained from a normal healthy subject not suffering from, being treated for, diagnosed, suspected of having, or at increased risk of developing, the disorder (see para. 104 of the specification). The present invention contemplates genomically editing primary human cells to cleave B2M gene sequences, as well as editing the genome of such cells to alter one or more additional target polynucleotide sequences. The disclosure provided by the applicant, in view of prior art, must encompass a wide area of knowledge to a reasonably comprehensive extent. In other word each of these, aspect must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such Artisan.
Guidance of the Specification and The Existence of Working Examples:
The specification teaches designing gRNAs to target Cas9 to the B2M gene (FIG. 5A). Each guide was first tested for the ability to direct site-specific mutations in HEK293T cells. Using flow cytometry, we measured the efficiency of each gRNA to direct Cas9-mediated ablation of B2M surface expression 72 hours post-transfection (FIG. 5B). We observed that B2M was abrogated in-7% (1.02 SEM, n=3) to 48% (.+-.80 SEM, n=3) of HEK293T cells depending upon the gRNA utilized (FIG. 5C and FIG. 6A). Similar results were observed using the Surveyor assay, with gRNA-specific mutation frequencies of 0-26% in HEK293T cells (FIG. 6B). It is further disclosed that variation in the efficiency with which a specific gRNA directed Cas9- mediated ablation was observed, even between gRNAs targeting the same exon or nearly overlapping sites (FIG. 5A-E) indicating that on-target efficiency of site directed mutation is highly gRNA dependent as previously noted by Hsu et al (Nat Biotechnology. 2013 Sep;31(9):827-32). The specification further teaches that the activity of the CRISPR/Cas9 system is remarkably variable in different human cell types, with the same gRNA exhibiting highly efficacious on target mutagenic activity in HEK293T cells but little activity in CD4+ T cells. In contrast, the targeting efficacy in K562 cells and CD34+ HSPCs was comparable. Moreover, consistent with previous reports (Hsu et al., 2013) the specification discloses that the efficiency of the CRISPR/Cas9 system was gRNA specific, as even gRNAs with partially overlapping sequences within the same exon displayed significantly different targeting efficiencies. Further, a dual gRNA approach yielded increased gene ablation efficacy in both CD4..+ T cells and CD34.sup.+ HSPCs leading to predicted deletions at the targeted loci (see para. 247). Figure 9A and 9B demonstrate potential off-target sites identified in CCRS5 homologue CCR2 and analysis of events detected at the single off-target site in which mutagenesis was significantly detected above background. Figures 10A, 10B, 10C and 10D demonstrate that CCR5-edited CD34+ HSPCs retain multi-lineage potential. Representative FACS plot showing human hematopoietic cell (hCD45+) engraftment and multi-lineage reconstitution at 12 weeks post-transplantation in the bone marrow (FIG. 10B) and spleen (FIG. 10C) of NSG recipient mice.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The claimed method encompasses administering cell to a subject in need thereof to a subject, said method comprising altering a target polynucleotide sequence associated with a disorder in a cell or a population of cells ex vivo by contacting the polynucleotide sequence, wherein the disorder includes any genetic disorder that is a monogenic disorder or a multigenic disorder including Alzheimer’s disease, polycystic ovary syndrome, inflammatory diseases¸ cardiovascular disease, Huntington’s disease, thromboembolic disease, neurovascular diseases, psychosis, multiple sclerosis, schizophrenia, schizoaffective disorder, and bipolar disorder, colorectal cancer, a disorder associated with a SNP adjacent to the AKT1 gene locus, an eating disorder, autoimmune disease, fibrostenosing disease in patients with Crohn’s disease, and Parkinson’s disease (see para. of the specification). The specification further contemplates disorder includes human immunodeficiency virus (HIV) infection or AIDS or cancer of different etiology and pathology (see para. 156 of the specification). However, the specification provides no examples of administering any genetically modified cells or the population of cells for the treatment of any disease, any infection or cancer of different etiology and pathology using the cells of the invention that would enable the method as claimed.
A Lack of Nexus between Administration and Treatment or Prevention
The breadth of disease encompasses, for example, an immunodeficient disease, a nervous system disease or a hematopoietic disease. However, a review of the instantly filed specification and the art, the skilled artisan would find that administering the genetically modified cells or population of cells of the claimed method for the purposes of treating or preventing would not treat diseases such as Huntington's disease, Alzheimer's disease, ALS, spinal muscular atrophy, brain tumors, colon cancer and leukemia, HIV or any bacterial/viral infection. The art teaches while Huntington's disease, Alzheimer's disease, and ALS are nervous system diseases, there is no nexus between their individual etiologies and pathologies and the claimed method, i.e. introducing a genetically modified cells or population of cells to a subject to treat a disease. Alzheimer's disease is caused by accumulation of ~-amyloid plaques interweaved with tau monofilaments. ALS is caused by progressive degeneration and eventual death of motor neurons in the brain and spinal cord. Huntington's disease is a purely genetically inherited disease potentiated by excessive CAG repeats that result in the death of neurons (Madireddy et al Journal of Neuroscience and Neurological Disorder, 2019, 148-161). Lastly spinal muscular atrophy is caused by a mutation in the SMN1 gene resulting in decreased neural innervation (d’Ydewalle et al Neurotherapeutics (2015) 12:303-316). Thus, while all of the above diseases are classified as nervous system diseases, there exists no nexus, either in the art or the specification, between the recited diseases and the genetically modified cells of the claimed invention. The claimed method encompasses all disorder associated with expression of a polynucleotide sequence is cleaved in a subject that could occur in a subject, and the skilled artisan would find that such a breadth would be unpredictable given the teachings of the specification, the breadth of cells to be administered and the lack of teachings in the art that would support the breadth of the claimed invention.
In the instant case, neither prior art nor instant specification provide any nexus recited in the claims between "introducing a genetically modified cell or a genetically modified cells to the subject" that results in preventing or treating any disorder in subject. The claimed method has operable step that is the administration of the genetically modified cells There is no recitation of how the subject is being treated or provided any treatment or prevention of broad genus of disorder encompassed by the breadth of the claim by the administration of said cells.
Unpredictability of multiplex gene editing
The claims encompass (a) altering any target polynucleotide sequence associated with any disorder in any cell or a population of cells ex vivo by contacting the polynucleotide sequence with any Cas protein and at least one ribonucleic acid, wherein the ribonucleic acid directs Cas protein to and hybridizes to any target motif of the target polynucleotide sequence associated with the disorder, wherein the target polynucleotide sequence associated with the disorder is cleaved; (b) altering a target B2M polynucleotide sequence in the cell or population of cells ex vivo by contacting the target B2M polynucleotide sequence with a Cas protein and at least one ribonucleic acid selected from the group consisting of SEQ ID NOs: 9-23 and 419-2609.
The state of the art before and after filing of instant application teaches multiplex gene editing significantly increases the risk of unintended chromosomal deletions and translocations compared to making a single edit. In this regard, Aussel et al (Nature Communication, 2025, 7208, 1-5 and references therein) teaches CRISPR/Cas system can also induce other SVs, including translocation between homologous chromosomes that results in an acentric and a dicentric chromosome, large deletions following two cleavage events on the same chromosome, and translocations between two different (heterologous) chromosomes, e.g. upon simultaneous cleavage of the target site and an OT site (see Frock, et al. Nat. Biotechnol. 33, 179–186, 2015). As any type of genomic aberration, from point mutations to large-scale chromosomal rearrangements, can ultimately lead to hazardous cellular consequences (see page 1, col. 2, last para to page 2, col. 1, para. 1 and Hunt et al Hum Genet . 2023 Apr 24;142(6):705–720, table 2). Kalter et al (Mol Ther Nucleic Acids . 2025 Jul 17;36(3):102636 and references therein) teaches that while CRISPR-Cas system is highly efficient and versatile, adverse editing events at unintended sites, known as off-target activity (OTA), remains a significant safety concern. OTA can occur when the CRISPR-Cas complex associates genomic loci with high sequence identity to the on-target sites, and is further complicated by the tolerance of DNA and RNA base bulges by CRISPR-Cas complexes (Figure 3A). In the instant case, claims are broadly require altering any target polynucleotide sequence associated with any disorder by contacting the polynucleotide sequence with any Cas protein and at least one ribonucleic acid, wherein the ribonucleic acid directs Cas protein to and hybridizes to any target motif of the target polynucleotide sequence associated with the disorder. The guidance provided in the specification is limited to CCR5-edited CD34+ HSPCs using specific gRNA as set forth in Fig. 1 and Cas9. Ellwanger et al (Virus Research, 2020, 286, 198040, 1-24) in a post filing publication states “participation of CCR5 in different viral infections is complex and varied and, therefore, cannot be generalized. This article also pointed out neglected gaps in knowledge involving CCR5 that should be addressed in future studies” (see page 16, col. 2, last para.). The study of Ellwanger clearly shows that targeting CCR5 to treat or prevent genus of viral infection was not predictable and neither prior art or instant specification provide any guidance to provide art recognized unpredictability. The specification is silent on altering genus of target polynucleotide sequence associated with the broad class of disorder in a cell or a population of cells ex vivo encompassed by the breadth of the claim such that by contacting the broad class of polynucleotide sequence associated with plurality of different disease with a Cas protein and at least one ribonucleic acid, wherein the ribonucleic acid directs Cas protein to and hybridizes to a target motif of the target polynucleotide sequence associated with the disorder, wherein the target polynucleotide sequence associated with the disorder is cleaved. The art teaches that cells with B2M-KO lack Major Histocompatibility Complex (MHC) class I on their surface avoid detection and killing by cytotoxic T cells, which typically target cells presenting antigens via MHC-I. However, the art teaches NK cells act as a backup surveillance system and possess a mechanism called "missing-self" recognition. In this regard, Sun teaches B2m-/- cells are rapidly rejected by wild-type NK cells in chimeric mice following viral infection (Fig. 4a-b). (Sun et al J Immunol. 2008 Dec 1;181(11):7453–7457. ). It is known in art that B2M is component of MHC class I complex that helps the immune system’s T cells to recognize cancer cells. However, art recognizes that editing B2M gene is also expected to evade the host immune system that may contribute to resistance to standard immunotherapies as evident from the teaching of Han (Frontiers of Immunology, 2025, 16:1512509, 1-15, and references therein, see page 4, col. 2, para. 1). In view of foregoing, it is apparent that there is no nexus between the in vitro examples of producing genetically modified CD34+ HSC or T cells of the invention and the in vivo delivery of genetically modified cell or population of cell that is provided by administering said genetically modified cells as claimed via any route to treat or prevent a disorder selected from a genetic disorder, infection and cancer. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
Unpredictability of introducing cell or population of cells into the subject
The claims encompass administering the genetically altered cell to a subject in need thereof intended to treat a cancer that includes a solid tumor, from which the cancer pathology then spreads and blood born cancer such a leukemia which are diffuse. The claimed invention relies upon targeting of the genetically modified cells to the breadth of species that encompass cancer. There are no teachings in the specification that would teach or suggest that the genetically modified cells or population of cells , such as any somatic cell, hepatocyte or pluripotent cells would be able to treat hematologic cancers such as leukemia, myeloma or lymphoma or cancer which comprise a solid tumor. The art teaches “Despite major advances, the current approach to face cancer treatment is still reductionist. Targeting single molecular abnormalities or cancer pathways has achieved good clinical responses that have modestly affected survival in some cancers. However, targeting a single hallmark or pathway with a single drug ("magic bullet") will not likely lead to cancer cure. We predict that drug combinations against several molecular alterations or cancer hallmarks, in a way that is similar to what we have done with HIV treatment, might be a promising therapeutic strategy to treat cancer in the near future." (Zugazagoitia et al., 2016, Clin .Therapeutics, Vol. 38, 1551-1566, see page 1564 col. 1 para. 2 lines 1-12). Again, there is no nexus between the in vitro examples of producing genetically modified cells of the invention and the in vivo therapy that is provided by administering said genetically modified cells. The claims thus encompass treating or preventing any genetic, viral or cancer by administering via any route the recited genetically modified cell or population of cells. However, in view of the teachings of prior art, there would be significant unpredictability regarding just delivering somatic cells to the brain of a patient. Further, there exists no nexus, by which administered somatic cells can actually treat cancer and neither the art or the specification provides any mechanism of action by which the administered genetically modified somatic cells would provide any treatment or therapeutic effect to the breadth of cancers that would enable the claimed method. The claims encompass xenogeneic transplantation of genetically modified cell or population of cells. The specification fails to provide any predictable guidance as to how the genetically modified cell or population of cell from one subject that is edited for B2M and any target polynucleotide sequence associated with the disorder would be engrafted in another subject as required by the method of treating or preventing a disorder associated with expression of the polynucleotide sequence. For instance, Frederiksen (Front. Genome Ed. 2024, 6:1403395. 1-17 and references therein) teaches transplantation of immune-evasive hESCs (B2M-/-) into immune competent BALB/c mice resulted in complete rejection within 11 days, with clear immune infiltration of T-cells on day 8. The results reveal that knockout of B2M and CIITA together with species specific expression of CD47 are insufficient to prevent rejection in an immune competent and xenogeneic context (page 1, last para.). An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled for the claimed inventions. An artisan of skill would have required undue experimentation to practice the invention, without reasonable expectation of success as supported by the observations in the art record.
Response to arguments
Applicant disagree with the rejection arguing the amended claims recite a method of administering cells to a subject in need of such cells. The method involves altering a target polynucleotide sequence ex vivo by contacting the polynucleotide sequence with a Cas protein and at least one ribonucleic acid, wherein the target polynucleotide sequence is cleaved. The specification describes the use of the CRISPR/Cas9 system to target two clinically relevant genes, B2M and CCR5. Thus, the application enables the targeting of a polynucleotide sequence (e.g., CCR5) associated with a disorder (e.g., HIV infection), with a Cas protein and at least one ribonucleic acid. The modified cells may then be transplanted or administered into a subject, e.g., a mouse. See id. at paragraph [0244]. Applicants’ arguments have been fully considered, but are not found persuasive.
In response to applicant’s argument that instant specification enables the use of the CRISPR/Cas9 system to target two clinically relevant genes, B2M and CCR5, it is noted that none of the claims require use of the CRISPR/Cas9 system to target genes, B2M and CCR5 as argued by the claims. Further, none of the claim require even engraftment of the genetically modified cell or population of cell in the subject to make use of the inevntion. As stated in previous office action, the claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention. The claims recite a method of administering cells to a subject in need of such cells. The specification teaches intended use in the subject in need thereof suffering from, being treated for, diagnosed with, suspected of having, or at increased risk of developing, the disorder such as a genetic disorder, an infection (e.g., HIV or AIDS), and cancer. The cells can also be obtained from a normal healthy subject not suffering from, being treated for, diagnosed, suspected of having, or at increased risk of developing, the disorder (see para. 104 of the specification). In view of foregoing, it is apparent that the only intended use of administering the cells to a subject in need of such cells is to treat or prevent disorder that is selected from the group consisting of any genetic disorder, any infection, and any cancer of different etiology and pathology.
The guidance provided in the specification is limited to in vivo reconstitution potential of HSPCs following CRISPR/Cas9 targeting of xenotransplantation of CCR5 -edited (Cas9 + crCCR5 D+Q) CD34+ HSPCs into immunodeficient NOD-PrkdcScid-IL2rγnull(NSG). The breadth of disease encompasses, for example, an immunodeficient disease, a nervous system disease or a hematopoietic disease.
However, a review of the instantly filed specification and the art, the skilled artisan would find that administering the genetically modified cells or population of cells of the claimed method for the purposes of treating or preventing would not treat diseases discussed in the previous office action mailed on November 5, 2025 (see page 7 of the nonfinal office action). The claimed method encompasses all disorder associated with expression of a polynucleotide sequence is cleaved in a subject that could occur in a subject, and the skilled artisan would find that such a breadth would be unpredictable given the teachings of the specification, the breadth of cells to be administered and the lack of teachings in the art that would support the breadth of the claimed invention. The breadth of disease encompasses, for example, an immunodeficient disease, a nervous system disease or a hematopoietic disease. However, a review of the instantly filed specification and the art, the skilled artisan would find that administering any specie of genetically modified cells or population of cells of the claimed method for the purposes of treating or preventing would not treat diseases such as Huntington's disease, Alzheimer's disease, ALS, spinal muscular atrophy, brain tumors, colon cancer and leukemia, HIV or any bacterial/viral infection. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
It is emphasized that instant specification is silent on altering genus of target polynucleotide sequence associated with the broad class of disorder in a cell or a population of cells ex vivo encompassed by the breadth of the claim such that by contacting the broad class of polynucleotide sequence associated with plurality of different disease with a Cas protein and at least one ribonucleic acid, wherein the ribonucleic acid directs Cas protein to and hybridizes to a target motif of the target polynucleotide sequence associated with the disorder, wherein the target polynucleotide sequence associated with the disorder is cleaved. The art teaches that cells with B2M-KO lack Major Histocompatibility Complex (MHC) class I on their surface avoid detection and killing by cytotoxic T cells, which typically target cells presenting antigens via MHC-I. However, the art teaches NK cells act as a backup surveillance system and possess a mechanism called "missing-self" recognition. In this regard, Sun teaches B2m-/- cells are rapidly rejected by wild-type NK cells in chimeric mice following viral infection (Fig. 4a-b). (Sun et al J Immunol. 2008 Dec 1;181(11):7453–7457. ). It is known in art that B2M is component of MHC class I complex that helps the immune system’s T cells to recognize cancer cells. However, art recognizes that editing B2M gene is also expected to evade the host immune system that may contribute to resistance to standard immunotherapies as evident from the teaching of Han (Frontiers of Immunology, 2025, 16:1512509, 1-15, and references therein, see page 4, col. 2, para. 1). In view of foregoing, it is apparent that there is no nexus between the in vitro examples of producing genetically modified CD34+ HSC or T cells of the invention and the in vivo delivery of genetically modified cell or population of cell that is provided by administering said genetically modified cells as claimed via any route intended to treat or prevent a disorder selected from a genetic disorder, infection and cancer. An artisan would have to perform undue experimentation to make and use the invention, without reasonable expectation of success.
Therefore, in view of the fact patterns of the instant case, and the ground of rejection outlined by the examiner, applicants' arguments are not compelling and do not overcome the rejection of record.
Maintained-Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 50-60 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 50 is vague and indefinite to the extent the metes and bounds of the target polynucleotide sequence associated with the disorder in a cell could not be ascertained. Specifically, the term “associated with” is unclear. While the claim states that the association is via expression it is not clear what is encompassed by the association. The association could be translationally, transcriptionally, cellularly or molecularly. Further, this association may be upstream or downstream of a target sequence affecting the expression of the target polynucleotide. Therefore, the scope of the claim could not be ascertained. A direct recitation of expression of a target polynucleotide (for example CCR5) that is responsible for a specific disease (for example HIV) would obviate the basis of the rejection. Claims 41-50 are directly or indirectly depend from the rejected base claim. Appropriate correction is required.
Response to arguments
Applicant disagree with the rejection arguing "a target polynucleotide sequence associated with a disorder," is fully supported by the application as originally filed. Specifically, the application describes a target polynucleotide sequence that is associated with a disorder may be a polynucleotide sequence corresponding to a genomic sequence which contains a disease associated single polynucleotide polymorphism. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is emphasized that instant rejection is not directed to limitation not fully supported by the specification as argued by the applicant. The rejection pertains to metes and bounds of the phrase “a target polynucleotide sequence associated with the disorder in a cell” could not be ascertained. It is unclear as to what is encompassed by the association. As stated in previous office action, a direct recitation of a target polynucleotide of CCR5 corresponding to a genomic sequence of CCR5 which contains a HIV associated single polynucleotide polymorphism would obviate the basis of the rejection.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Meissner et al (Methods in Enzymology, 2014, Volume 546 chapter 13, 273-293, a8oaok ISHN: SPSOT S801 S842 17/07/2014) teaches Meissner et al teach an isolated primary human CD4+ T cells whose genome comprises a deletion of a 2.2 kb of contiguous stretch of genomic DNA of the beta2-microglobulin gene in human primary CD4+ T cells with the aid of a Cas protein in combination with two guide sequences similar to one disclosed in the instant application (see page 275, para. 3, page 276, last paragraph; figure 13.1, 13.5). It is further disclosed that deletion of 2.2 kb stretch of the beta2-microglobulin gene results in lack of surface expression of MHC molecule and the length of the deleted fragment corresponds to that of the deletion (2.2 kb) disclosed in the instant specification (see figure 1 of instant specification).
Musunuru et al (WO2014/165825, dated 10/09/2014) teaches a primary human cell or population of primary human cells (para. 4} comprising a genome in which the beta?-ricroglobulin (B2M) gene on chromosome 15 is deleted (edited) (para. 102, 108, 113, 136; figure 4D:), thereby eliminating surface expression of MHC Class | molecules in the cell or population of cells (para. 136, 239), wherein the contiguous stretch of genomic DNA has been deleted by contacting the ecli or population of human cells with a Cas? protein (para. 244)) or a nucleic acid encoding the Cas® protein and a pair of ribonucleic acids (para @, 10,43, 244, wherein cells are selected from the group consisting of a stem cell (para, 4, 8}, a pluripotent cell (para. 1¢1), a progenitor cells (para 181), a hematopoietic stem and/or progenitor cell, a CD344 mobilized peripheral blood cell (paragraph (181), a CD34 + cord blood cell (paragraph 183), a CD34+ bone marrow cell (para 16)), a Ch34+ 38-Lineage-CD90-HCD45R A- cell (para 181}, and a CD34+ hematopoietic stem and/or progenitor cell a CD4+ T cell, a hepatocyte (para 1S1) and wherein cells are obtained from a subject (para. 171, 173} suffering from (para. 1733), being treated for diagnosed with. at risk of developing, or suspected of having a disorder selected from the group consisting of a genetic disorder (para 24223, a HIV infection; para24, 242), and cancer (para.242)}.
Gussow et al (J. Immunol. 139 (9), 3132-3138, 1987) and NCBI accession no NG_012920.1 (07/08/2013, pages 1-6)/ Naldini et al (USPGPUB 20190032049 effective filing date 10/24/2014) teaches the nucleic acid sequence that is 100% identical to SEQ ID NO: 16, identified as Homo sapiens beta2microglobulin (B2M), on chromosome 15 and 100% identical to SEQ ID NO: 21 of the instant application to nucleic acids 5093-5112 of the sequence of accession NG_012920 identified as Homo sapiens beta2microglobulin (B2M), on chromosome 15 is known in art as evidenced by (Gussow or Naldini/NG 012920.1).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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